Studies on the hypolipdemic and estrogenic activities of 2,8-dibenzylcyclooctanone and its analogues.
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Biomedical subjects
Publications and source records attributed to M L Givner.
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A rhythmic antifertility effect of a luteinizing hormone-releasing hormone (LH-RH) analog, [D-Ala6-des-Gly-NH210]-LH-RH-ethylamide (AY-25,205), administered intramuscularly every 3rd day staring in the afternoon of diestrus, was demonstrated in 4-day cyclic rats. The antifertility effect was achieved for a period of approximately four cycles when the females were allowed constant cohabitation with fertile males except for 24 hours following treatment. Unrestricted cohabitation resulted in some matings and pregnancies in the group treated every 3rd day and also in some of the groups treated every 4th day with restricted cohabitation. The antifertility effect of AY-25,205, with unrestricted cohabitation, disappeared when the second treatment was given 4 days after the first. It is presumed that the antifertility effect of AY-25,205 was achieved through its capacity to induce ovulation at a physiologically "wrong time" (i.e., 1 day before the expected day of proestrus) and through its effect on mating behavior. The present experimental models suggest that AY-25,205 or similar analogs could be potentially useful for a more reliable rhythm method of birth control in humans, by timing ovulation and narrowing the fertile period of the cycle.
An in vivo method for the determination of biological potency of luteinizing hormone-releasing hormone (LH-RH) antiserum is described. The procedure involves antiserum blockade of LH-RH induced ovulation in immature rats primed with pregnant mare's serum. A modified method for the induction of LH-RH antibodies in rabbits is also detailed.
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A novel method is described for the measurement of nanogram quantities of clogestone acetate (3beta, 17alpha-dihydroxy-6-chloropregna-4,6-dien-20-one 3,17-diacetate) in serum:clogestone acetate (CgAc) is converted to chlormadinone acetate in the presence of wheat germ lipase and hydroxysteroid dehydrogenase. The ketonic steroid formed is then incubated with rat uterine cytosol and 3-H-progesterone. The concentration of 3CgAc is estimated from a standard curve derived by incubating cytosol with 3-H-progesterone and varying amounts of chlormadinone acetate. The statistically validated method has been used for the estimation of serum CgAc in humans and dogs given an oral dose of the steroid. The radioreceptor assay (RRA), has practical advantages over related techniques such as radioimmunoassay (RIA) especially with respect to the developmental work. This is the first time that a quantitative assay of a progestin by the tissue receptor approach has been described.
Pro-oestrous rats, treated with fluphenazine dihydrochloride to block ovulation, were used to compare the ovulation-inducing activity of synthetic LH-RH with one of its analogues, [D-Ala-6, des-Gly-NH2-10]-LH-RH ethylamide (AY-25,205). The lowest dose of LH-RH which produced a significant response was 125 ng compared with 2.9 ng AY-25,205. Statistical analysis of the data showed that AY-25,205 was approximately thirty-six times more potent than LH-RH. Treatment with AY-25,205 also induced partial ovulation in metoestrous rats (80 or 160 ng/rat) and apparently normal ovulation in dioestrous rats (10 to 160 ng/rat). The compound (160 ng) failed to induce further ovulation in oestrous rats which ovulated during the previous night. Advancement of premature ovulation in dioestrous rats with AY-25,205 prevented mating behaviour and pregnancy during the treatment cycle. The antifertility effect of the compound disappeared during the following cycle.
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We present the cases of two patients with short-bowel syndrome who failed to achieve therapeutic cyclosporine serum concentrations on oral drug but were successful on intravenous administration. One patient received cyclosporine after renal transplantation for renal failure secondary to enteric oxalosis; the second received cyclosporine for active Crohn's disease. The rapid bowel transit time was the critical factor in limiting cyclosporine absorption in both cases. In studying oral and intravenous pharmacokinetic profiles, we support a zero-order kinetic model for oral cyclosporine absorption.